The principal objective of this research is to develop new methods for assessing lung microstructure at alveolar length scales, using hyperpolarized noble-gas magnetic resonance imaging (MRI). The non- radioactive noble-gas isotopes helium-3 (3He) and xenon-129 (129Xe) were introduced in the mid-1990s as inhaled contrast agents for MRI, and have since shown substantial potential for providing medically relevant information about lung diseases such as emphysema and asthma, to a degree inaccessible by other imaging modalities. In particular, diffusion MRI of the inhaled hyperpolarized gas shows promise for detecting disease- related changes in lung microstructure earlier than high-resolution computed tomography (CT) or standard pulmonary function tests. The advantage of diffusion MRI is that it allows one to probe length scales that are much smaller than a conventional imaging pixel;the effective "resolution" of the technique depends on the time over which diffusion effects are measured. Very-short time scales, corresponding to alveolar dimensions in the lung, are very challenging to reach using existing hyperpolarized-gas diffusion MRI methods. Accordingly, the vast majority of in-vivo hyperpolarized-gas diffusion studies to date have been performed at longer time scales corresponding to the size of alveolar clusters, or acini. The basic premise of the proposed research is that diffusion measurements at very short time scales will be significantly more sensitive to early and incremental disease- related changes in lung microstructure at the sub-acinar level. The specific research aims are to develop, test, and optimize new MRI pulse-sequence strategies for measuring very-short-time diffusion of inhaled hyperpolarized gas;to establish the ability of the optimized techniques to make quantitative structural measurements at alveolar length scales in model systems;and to apply the new techniques in normal and diseased animal lungs to evaluate their potential for detecting small changes in lung microstructure at the alveolar level, including alterations in the surface-to-volume ratio of acinar air spaces. Successful completion of these aims will open up exciting new avenues for clinicians and scientists to investigate the pathophysiology of lung disease, monitor disease progression, and develop effective treatments. PUBLIC HEALTH RELEVANCE: The principal objective of the proposed research is to develop methods for non-invasively measuring details of microscopic lung structure using magnetic resonance imaging. Application of these methods may be used for early detection of serious lung diseases such as emphysema and will provide a tool for medical researchers to better investigate the causes and potential treatments of lung disease.